{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:57:14Z","timestamp":1768507034195,"version":"3.49.0"},"posted":{"date-parts":[[2023,9,5]]},"group-title":"Neuroscience","reference-count":63,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,9,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Chronic psychostimulant use can cause long lasting changes to neural and cognitive function that persist even after long periods of abstinence. As cocaine users transition from drug use to abstinence, a parallel transition from hyperactivity to hypoactivity has been found in orbitofrontal-striatal glucose metabolism, and striatal D2\/D3 receptor activity. Targeting these changes pharmacologically, using highly selective dopamine D3 receptor (D\n                  <jats:sub>3<\/jats:sub>\n                  R) antagonists and partial agonists, has shown significant promise in reducing drug-taking, and attenuating relapse in animal models of cocaine and opioid use disorder. However, much less attention has been focused on treating inflexible and potentially maladaptive non-drug behaviors following chronic psychostimulant use. Here we tested the selective D\n                  <jats:sub>3<\/jats:sub>\n                  R antagonist VK4-116 as a treatment for the long-term behavioral inflexibility in abstinent male and female rats with a prior history of chronic cocaine use. Rats were first trained to self-administer cocaine (0.75 mg\/kg\/reinforcer) or a sucrose liquid (10%, .04 mL\/reinforcer) for 2 weeks (FR1 schedule, max 60 reinforcers in 3 hrs\/ day), followed by 4 weeks of abstinence. Cognitive and behavioral flexibilities were then assessed using a sensory preconditioning (SPC) learning paradigm. Rats were given an VK4-116 (15 mg\/kg, i.p.) or vehicle 30 mins prior to each SPC training session, thus creating four drug-treatment groups: sucrose-vehicle, sucrose-VK4-116, cocaine-vehicle, cocaine-VK4-116. The control groups (sucrose-vehicle, sucrose-VK4-116) demonstrated significant evidence of flexible SPC behavior, whereas cocaine use (cocaine-vehicle) disrupted SPC behavior. Remarkably, the D\n                  <jats:sub>3<\/jats:sub>\n                  R antagonist VK4-116 mitigated this cocaine deficit in the cocaine-VK4-116 group, demonstrating flexible SPC to levels comparable to the control groups. These preclinical findings demonstrate that highly selective dopamine D\n                  <jats:sub>3<\/jats:sub>\n                  R antagonists, particularly VK4-116, show significant promise as a pharmacological treatment for the long-term negative behavioral consequences of cocaine use disorder.\n                <\/jats:p>","DOI":"10.1101\/2023.09.03.556083","type":"posted-content","created":{"date-parts":[[2023,9,5]],"date-time":"2023-09-05T22:05:18Z","timestamp":1693951518000},"source":"Crossref","is-referenced-by-count":1,"title":["The selective D3-Receptor antagonist VK4-116 effectively treats behavioral inflexibility in rats caused by self-administration and withdrawal from cocaine"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2635-5638","authenticated-orcid":false,"given":"Marios C.","family":"Panayi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shohan","family":"Shetty","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Micaela","family":"Porod","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisette","family":"Bahena","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zheng-Xiong","family":"Xi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy Hauck","family":"Newman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8180-0701","authenticated-orcid":false,"given":"Geoffrey","family":"Schoenbaum","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023090813551530000_2023.09.03.556083v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jml.2012.11.001"},{"key":"2023090813551530000_2023.09.03.556083v1.2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b00776"},{"key":"2023090813551530000_2023.09.03.556083v1.3","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4371-11.2012"},{"key":"2023090813551530000_2023.09.03.556083v1.4","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhr354"},{"key":"2023090813551530000_2023.09.03.556083v1.5","doi-asserted-by":"publisher","DOI":"10.1037\/0097-7403.34.2.202"},{"key":"2023090813551530000_2023.09.03.556083v1.6","unstructured":"Fox, J. , & Weisberg, S. 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